Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model

• Type of Material: Article
• Authors: Ria Goswami, Duke University; Ashley N. Nelson, Duke University; Joshua J. Tu, Duke University; Maria Dennis, Duke University; Liqi Feng, Duke University; Amit Kumar, Emory University; Jesse Mangold, Duke University; Riley J. Mangan, Duke University; Cameron Mattingly, Emory University; Alan D. Curtis, University of North Carolina Chapel Hill; Veronica Obregon-Perko, Emory University; Maud Mavigner, Emory University; Justin Pollara, Duke University; George M. Shaw, University of Pennsylvania; Katharine J. Bar, University of Pennsylvania; Ann Chahroudi, Emory University; Kristina De Paris, University of North Carolina Chapel Hill; Cliburn Chan, Duke University; Koen K. A. Van Rompay, University of California Davis; Sallie R. Permar, Duke University
• Language: English
• Date: 2019-09-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Goswami et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/mBio.01971-19
• Title of Journal or Parent Work: MBIO
• Volume: 10
• Issue: 5
• Grant/Funding Information: BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy grant UM1AI126620 (to K.J.B.); Penn Center for AIDS Research Viral and Molecular Core grant P30 AI045008 (to K.J.B.); The work was supported by National Institutes of Health grants P01 AI117915 (to S.R.P. and K.D.P.), 5R01 AI106380 (to S.R.P.), T32 5108303 (to A.D.C.), T32-CA009111 (to A.N.N.) and 5R01-DE025444 (to S.R.P.); Several protein antigens for BAMAs and ELISAs were generously provided by Barton Haynes, who is supported by NIH NIAID Division of AIDS UM1 grant AI100645, for the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID), and were produced at the Duke Human Vaccine Institute (DHVI) Protein Production Facility.; CARE: Delaney Collaboratory for AIDS Eradication grant UM1AI126619 (to K.J.B.); The Center for AIDS Research at Emory University is supported by grant P30AI050409.; Office of Research Infrastructure Program/OD (grant P51OD11107; to CNPRC); The research contributions by A.D.C. and K.D.P. were supported by the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR) and NIH-funded program grant P30 AI050410.
• Keywords: Life Sciences & Biomedicine; Science & Technology; Responses; analytical treatment interruption; Replication; High frequency; Viral load; Neutralizing antibody; pediatric HIV cure; MAMU-A-ASTERISK-01; HIV reservoir; HIV-1 Remission; Reservoir; Animal models; SIV; Microbiology; SHIV
• Research Categories: Health Sciences, Rehabilitation and Therapy; Health Sciences, Immunology; Biology, Microbiology

Abstract

To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre- ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure.